Lysosomal genes contribute to Parkinson’s disease near agriculture with high intensity pesticide use

Parkinson’s disease (PD), the second most common neurodegenerative disorder, develops sporadically, likely through a combination of polygenic and environmental factors. Previous studies associate pesticide exposure and genes involved in lysosomal function with PD risk. We evaluated the frequency of variants in lysosomal function genes among patients from the Parkinson’s, Environment, and Genes (PEG) study with ambient pesticide exposure from agricultural sources. 757 PD patients, primarily of White European/non-Hispanic ancestry (75%), were screened for variants in 85 genes using a custom amplicon panel. Variant enrichment was calculated against the Genome Aggregation Database (gnomAD). Enriched exonic variants were prioritized by exposure to a cluster of pesticides used on cotton and severity of disease progression in a subset of 386 patients subdivided by race/ethnicity. Gene enrichment analysis identified 36 variants in 26 genes in PEG PD patients. Twelve of the identified genes (12/26, 46%) had multiple enriched variants and/or a single enriched variant present in multiple individuals, representing 61% (22/36) of the observed variation in the cohort. The majority of enriched variants (26/36, 72%) were found in genes contributing to lysosomal function, particularly autophagy, and were bioinformatically deemed functionally deleterious (31/36, 86%). We conclude that, in this study, variants in genes associated with lysosomal function, notably autophagy, were enriched in PD patients exposed to agricultural pesticides suggesting that altered lysosomal function may generate an underlying susceptibility for developing PD with pesticide exposure. Further study of gene-environment interactions targeting lysosomal function may improve understanding of PD risk in individuals exposed to pesticides.


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Sex and gender has been included in our analysis which was self-reported during the Parkinson's, Environment, and Genes (PEG) study recruitment.
Race/Ethnicity has been included in our analysis which was self-reported during PEG recruitment.Education was measured by total years at school.Each participant had a mean weighted sum calculated for pesticide exposure.Age at diagnosis, race/ethnicity, gender, Parkinson's Disease (PD) duration at baseline, PD family history, school years, and study wave were leveraged as covariates for determining disease progression.
No randomization was performed.
This study used 757 PD patients from the PEG study.62% of the cohort was male (468/757) with an average age at PD diagnosis of 67.7 years (standard deviation 10.6 years, range 23-89 years), and primarily of White European/non-Hispanic (75%, 571/757) descent.
Written informed consent was obtained from all participants.All methods in this study were approved by the UCLA Institutional Review Board.
Participants in this study were originally enrolled in PEG study from Ritz et al. 2012.Briefly, participants were enrolled in two waves (PEG1 from 2001-2007and PEG2 from 2010-2014).All study participants were confirmed to have probable idiopathic PD and were seen at least once at baseline by a UCLA movement disorder specialist and most were seen repeatedly over follow-up.
Based on Illumina's recommendations for sequncing up to 96 samples per sequencing lane, we sequenced 786 samples across an entire flow cell.11 samples failed repeatedly during library preparation, thus only 757 samples were included in the study.
To avoid bias due to familial relationships, we excluded related family members from the analysis.To balance the PD and control cohorts with respect to population genetics, we excluded subjects that did not self report as European or Hispanic ancestry.
No replication dataset was generated although we did compare our results to another published PD cohort (Parkinson Progression Marker Initiative).
No blinding was performed.

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